Research: Our research group is interested in studying the genetic basis for thoracic and head and neck cancers. One research aim of our group is to identify and collects samples from younger patients who present with these tumors. We hypothesize that these patients may present with a less complex cytogenetic profile which may facilitate the identification of important tumor-specific gene alterations. For example, we recently identified the genetic basis for the most common type of malignant salivary gland tumor by cloning the chromosomal breakpoint of a t(11;19) translocation detected in three of our clinic patients who had either lung or parotid gland tumors. We have shown that this chromosomal rearrangement generates an oncogenic fusion protein between two novel genes, Mect1-Maml2 and we have now pursued the molecular basis for this new cancer marker. We have recently demonstrated the importance of the t(11;19) translocation in these tumors by observing that the t(11;19) rearrangement was the sole cytogenetic alterations in several cases, by demonstrating the ability of Mect1-Maml2 to induce foci formation in rat RK3E epithelial cell in vitro, and by the detection of Mect1-Maml2 in 75% of tumors studied to date. We have also begun studying the biological effect of Mect1-Maml2 expression and have shown that it can disrupt both Notch and cAMP/CREB signaling pathways. Recent mutational and global expression analyses, however, suggest that Mect1-Maml2 mediated tumorigenicity is linked predominantly to the aberrant activation of selected cAMP/CREB regulated genes. This data provides a direct genetic link between deregulation of cAMP/CREB pathways and epithelial tumorigenesis and suggests future therapeutic strategies for this group of salivary gland tumors. In addition, we have shown that sustained expression of Mect1-Maml2 is essential for tumor viability and RNAi inhibition induces cell death exclusively in cells that carry the t(11;19) rearrangement. Future work will help define a mouse model and candidate pre-clinical and clinical studies. In addition, we have studied the role of the RB tumor suppressor pathway in human cancer and have demonstrated that the RB/p16 tumor suppressor pathway is inactivated in 100% of small cell lung cancer (SCLC) and non-SCLC. We are currently interested in examining the interrelationships between RB/p16 and the cyclin D/ras pathways in neuroendocrine tumorigenesis by defining abnormalities in these pathways within the samples developed at the National Naval Medical Center. In another research aim, we have initiated a genetic analysis of 25 different mesothelioma tumor cell lines collected at our hospital for which we have matching primary tumor samples. We are analyzing the RB/p16 and NF2/merlin pathways in these samples and have also initiated a comprehensive cytogenetic analysis using spectral karyotyping combined with a high resolution SNP LOH and mRNA expression analysis. These data will provide clues for additional investigations to provide further insights into diagnosis and therapy for this difficulty malignancy.